This laboratory has developed a helper virus-free Herpes Simplex Virus (HSV-1) plasmid vector system for gene transfer into neurons. Using this system, we have begun to explore gene therapy approaches to specific neurological disorders, such as Parkinson's Disease (PD). We have shown that delivery of a HSV-1 vector that expresses human tyrosine hydroxylase into the partially denervated striatum in the 6-hydroxydopamine rat model of PD results in significant (64 percent) and long-term (1 year) behavioral recovery. Modifications to the vector particle have enhanced the utility of specific vector systems. First, the titers and infectivity of classical retrovirus vectors, lentivirus vectors, and other vector systems have been enhanced by pseudotyping with vesicular stomatitis virus (VSV) G protein. Recently, both we and other investigators have shown that HSV-1 vectors can be pseudotyped with VSV G protein and such vector particles can support gene transfer into neurons in the rat brain. Second, gene transfer has been targeted to specific types of cells by modifying the vector particle of classical retrovirus vectors or adenovirus vectors. Third, we have enhanced neural gene transfer and long- term expression by packaging vectors in the presence of mutations in specific HSV-1 proteins that affect the virion. The long-term goal of this proposal is to modify the HSV-1 vector particle to enhance its utility for human gene therapy of neurological disorders such as PD. The first specific aim will develop procedures for producing high titer HSV-1 vectors pseudotyped with VSV G protein. The second specific aim will target gene transfer to nigrostriatal neurons by modifying the HSV-1 vector particle to bind to specific receptors on these neurons. The third specific aim will enhance gene transfer and long-term expression by packaging vectors in the presence of mutations in specific HSV-1 proteins that affect the virion. These modified vector particles will be systematically characterized and then evaluated for gene transfer and expression in the rat brain.